Bupivaciane is a local anesthetic commonly used for the treatment of pain following elective orthopaedic surgery. Patients undergo pre-operative local anesthetic blocks of nerve structures that provide innervation to the operative site. Other options include anesthetic injection at the site of surgery, use of a catheter placed in the epidural space through the lumbar spine for continuous release of the agent and intra- articular indwelling catheters that release local anesthetic continuously for 48 hours at a pre-determined rate. Adding local anesthetics to the vast armamentarium of pain medications for post-op pain control has helped decrease the amount of narcotic use and abuse. However, these modalities have associated complications including inadequacy of the anesthetic block, epidural bleeds in patients that are anti-coagulated in the post-op period, and infection for intra-articular catheters open to the external environment. We propose the use of the novel sol gel technology for the time controlled release of Bupivacaine. Drug molecules are incorporated in nanosized pore channels and are released by diffusion through the aqueous phase that penetrates into these pores. The sol gels can be synthesized as monoliths or as 10 micrometer granules. At this stage, Bupivacaine has been successfully incorporated into the sol gels and exhibits a favorable elusion profile. Preliminary quantification of the in-vitro release rate for various sets of processing parameters has been determined. In vivo feasibility studies have indicated that a dose-dependent effect of bupivacaine administered via implantation of sol gel - bupivacaine particles exists up to 5 to 7 days. We propose to optimize the in vitro analysis and then conduct in vivo testing of the release of Bupivacaine from granules in three rat models, which have previously been used and validated for studying pain control. They include the widely used Brennan model of incisional pain, and two models relevant to orthopaedic conditions, namely a cervical root nerve injury model of neuropathic pain and a sciatic nerve block model. The research components of this study are as follows: (1) Optimization of in vitro release profile of Bupivacaine. (2) In vivo phase I to establish (a) the relationship between the in vitro and in vivo release profiles of bupivacaine from sol gels of various formulations, and, (b) the effective doses and the relationship among the administered doses of sol gel/bupivacaine and the behavioral response. (3) In vivo phase II in which the results of in vivo study I will now be used to perform experimentation on a larger scale, using each of the three models, in order to achieve statistical significance with two doses. In this Phase 2 study, in addition to testing the behavioral response, we will also collect the blood samples at specific times to determine systemic concentrations of bupivacaine to establish a dosing relationship. All data combined, i.e. the data of the in vitro release, the data obtained from the two phase in vivo studies using existing models for studying pain treatment, as well as data obtained separately and in other laboratories worldwide will then form the basis for designing the subsequent clinical study. Although we will analyze all our data in view of the intended clinical use, we will not yet undertake this work during the funding cycle proposed here. For the Veterans Affairs Medical Center patient population undergoing elective Orthopaedic surgery, the issues of shorter hospital stay, decreased post-operative narcotic usage, and increasing willingness to participate in physical therapy and meet rehab goals are crucial to attaining good outcomes. This proposal addresses these issues and is in line with the general trend of the healthcare market in targeting streamlined cost efficiency and decreasing health care expenditures PUBLIC HEALTH RELEVANCE: Narrative: This study is focused on assisting the Veterans Affairs population undergoing orthopaedic surgery. Local delivery of pain medication has the potential to increase pain control, minimize narcotic medications and maximize functionality.